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Objective Morphine is a potent analgesic.However, its clinical application is restricted due to morphine tolerance.The underlying mechanism is not fully understood.Glia are thought to be involved in morphine tolerance, and P2X7 purinergic receptor (P2X7R) has been implicated in neuron-glia communication and chronic pain.This study investigated microglia-expressed P2X7 receptor (P2X7R) and its downstream mechanisms underlying the induction of tolerance to morphine analgesia in rats.Methods Behavioral tests, SiRNA, Western Blotting, immunohistochemistry, ELISA and electrophysiology methods were used in this study.Results Chronic morphine treatment induced morphine tolerance and an increase in the expression of P2X7R and IL-18 by microglia, IL-18 receptor (IL-18R) by astrocytes and PKCγ by neurons in the spinal cord, respectively, which was blocked by a P2X7R antagonist or targeting siRNA.Meanwhile, the release of astroglial D-serine, a ligand for NMDA receptor, was increased by chronic morphine, which was attenuated by the D-serine degradation.The D-serine-mediated presynaptic mechanism may contribute to the potentiation of spinal pain-sensitive neurons by chronic morphine treatment.Conclusion The present study revealed multiple dialogues between glial and neuronal cells via cascades involving P2X7Rs, IL-18, D-serine, NMDARs and PKCγ in morphine tolerance, which may provide novel targets for preventing morphine tolerance.